NL2013149B1 - System for neurostimulation. - Google Patents

Abstract

The present invention relates to a system for neurostimulation at least comprising a plurality of electrodes (132) being adapted for generating an electrical stimulation field, analysis means (320) being adapted to analyze the Local Field Potential (LFP) of surrounding tissue and adjustment means (322) to adjust the direction and/or the shape of the electrical stimulation field based on the analysis of the Local Field Potential of surrounding tissue.

Description

System for neurostimulation

The present invention relates to a system for neurostimulation.

Implantable neurostimulation devices have been used for the past ten years to treat acute or chronic neurological conditions. Deep brain stimulation (DBS), the mild electrical stimulation of sub-cortical structures, belongs to this category of implantable devices, and has been shown to be therapeutically effective for Parkinson’s disease, Dystonia, Essential Tremor, Obsessive Compulsive Disorder, and Epilepsy. New applications of DBS in the domain of psychiatric disorders (clinical depression, anorexia nervosa, schizophrenia) are being researched. In existing systems, a lead carrying four ring electrodes at its tip is connected to an implantable pulse generator.

Currently, systems are under development with more, smaller electrodes using a technology based on thin film manufacturing. These novel systems consist of a lead made from a thin film based on thin film technology, as e.g. described in WO 2010/055453 A1. The thin film carries multiple electrodes to cover the distal tip with an array of electrodes, and is assembled into a lead. Such leads will enhance the precision to address the appropriate target in the brain and relax the specification of positioning. Meanwhile, undesired side effects due to undesired stimulation of neighboring areas can be minimized.

Leads that are based on thin film manufacturing are e.g. described by US 7,941,202 and have been used in research products in animal studies.

In existing systems, the DBS lead has e.g. four 1.5 mm-wide cylindrical electrodes at the distal end spaced by 0.5 mm or 1.5 mm. The diameter of the lead is 1.27 mm and the metal used for the electrodes and the interconnect wires is an alloy of platinum and iridium. The coiled interconnect wires are insulated individually by fluoropolymer coating and protected in a urethane tubing of a few tens of micron thick. With such electrode design, the current distribution emanates uniformly around the circumference of the electrode, which leads to stimulation of all areas surrounding the electrode.

The lack of fine spatial control over current and electric field distributions implies that stimulation easily spreads into adjacent structures inducing adverse side-effects in as much as 30% of the patients. To overcome this problem, systems with high density electrode arrays are being developed, hence providing the ability to steer the stimulation field to the appropriate target (hence the term steering brain stimulation).

The clinical benefit of DBS is largely dependent on the spatial distribution of the stimulation field in relation to brain anatomy. To maximize therapeutic benefits while avoiding unwanted side-effects, precise control over the stimulation field is essential.

During stimulation with existing DBS leads there is an option to use monopolar, bipolar, or even multipolar stimulation. Neurostimulator devices with steering brain stimulation capabilities can have a large number of electrode contacts (n > 10) that can be connected to electrical circuits such as current sources and/or (system) ground. Stimulation may be considered monopolar when the distance between the anode and cathode is several times larger than the distance of the cathode to the stimulation target. During monopolar stimulation in homogeneous tissue the electric field is distributed roughly spherical similar to the field from a point source. When the anode is located close to the cathode the distribution of the field becomes more directed in the anode-cathode direction. As a result the field gets stronger and neurons are more likely to be activated in this area due to a higher field gradient.

Although the exact mechanisms of DBS are unknown, it is hypothesized that polarization (de- and/or hyperpolarization) of neural tissue is likely to play a prominent role both for suppression of clinical symptoms, and for induction of stimulation-induced side-effects. In order to activate a neuron it has to be depolarized. Neurons are depolarized more easily close to the cathode than by the anode (about 3-7 times more depending on type of neuron, etc.).

Not only the accurate placement of the lead is crucial for the clinical success of deep brain stimulation for e.g. treating Parkinson’s Disease, but also configuration after implantation of a deep brain stimulation system. During post-operative “DBS programming”, a considerable balancing effort is required to create an electrical field which results in good symptom suppression, while not inducing side-effects. An additional issue, which clinicians have to deal with during DBS programming, is the electrical current consumption of the internal pulse generator. An energy efficient configuration is preferred. Especially the post-operative DBS programming is a complex and time-consuming task.

It is therefore an object of the present invention, to simplify the programming of a system for neurostimulation, especially in that the post-operative DBS programming is less complex and less time-consuming and especially to increase the accuracy of the treatment.

This object is solved according to the present invention with a system for neurostimulation with the features of claim 1. Accordingly, a system for neurostimulation comprises at least a plurality of electrodes being adapted for generating an electrical stimulation field, analysis means being adapted to analyze the Local Field Potential (LFP) of surrounding tissue and adjustment means to adjust the direction and/or the shape of the electrical stimulation field based on the analysis of the Local Field Potential of surrounding tissue.

By this the advantage is achieved that the post-operative programming of a neurostimulation is less complex and less time-consuming. By adjusting the provided electrical stimulation field on the basis of the Local Field Potential of surrounding tissue, the programming of the neurostimulation is simplified and less time is consumed for the programming process. Thus, the clinician and the patient - who is usually awake during the programming procedure - can finish the programming procedure in less time when compared to current available approaches. Thus, the post-operative programming is less exhaustive for the clinician and the patient. Furthermore, so far programming is done by trial and error, trying to quantify patient improvement by clinical assessment of symptom reduction. Flowever, in order to keep the duration of a programming within reasonable time, and to limit the strain to the patient, the clinician cannot explore all possible stimulation settings. For this reason, little certainty can be obtained that the best programming settings have been achieved. By using objective measurements such as LFPs as done according to the present invention and coupling programming to the analysis of these resulting LFPs, more optimal stimulation parameters can be discovered and confirmed. In this way, the therapeutic outcome can be improved with expectedly less effort.

Local Field Potentials (LFPs) are interpreted as the low frequency (< 500 Hz) fluctuations in extracellular electrical activity that results from the superposition of the neuronal spikes generated by a relatively large number of neurons in the surroundings of an electrode, also referred to as ensembles of neurons.

The medical system may be especially a system for deep brain stimulation.

The surrounding tissue may be brain tissue (in connection with deep brain stimulation) or for example any other neural tissue like the spinal cord. Also other applications can be possible like for cochlear implants, heart implants, visual implants and the like.

Moreover, the plurality of electrodes allows steering of the stimulation field such that the stimulation field may be adapted and conform with the target area. In particular, stimulation steering is enabled where the electric field is shaped such that tissue located along certain directions receives much less stimulation current than other adjacent tissue regions.

The lead may comprise at least 20 electrodes, especially approx. 30 to 128 electrodes, more especially approx. 40 electrodes. This number of electrodes allows the creation of stimulation field which conforms to the target region and which may be formed three-dimensionally and adapted to the target region. Only those regions that need to be stimulated may be covered by the stimulation field provided by the plurality of electrodes.

The electrodes may form a complex electrode array. This is helpful to create a stimulation field that is adapted to and conforms with the target region. A complex electrode array generally refers to an arrangement of electrodes at multiple non-planar or non-coaxial positions, in contrast to simple electrode array geometries in which the electrodes share a common plane or common axis.

An example of a simple electrode array geometry is an array of ring electrodes distributed at different axial positions along the length of a lead.

An example of a complex electrode array geometry, in accordance with this disclosure, is an array of electrodes positioned at different axial positions along the length of the lead, as well as at different angular positions about the circumference of e.g. lead of the neurostimulation system.

The system may comprise recording electrodes. By means of the recording electrodes, the LFP of the surrounding tissue may be recorded. In particular, the advantage can be achieved that the LFP can be recorded with one lead carrying the electrodes and that no further recording lead needs to be used. Furthermore, the recording can be more accurate as the system itself can measure the LFP of the surrounding tissue with respect to its electrodes, which is far more accurate than using a separate recording system.

The recording electrodes may be at least partially a part of the plurality of electrodes, especially wherein the plurality of electrodes is adapted for both stimulation and recording. This simplifies the manufacturing process and furthermore, this increases the accuracy of the recording, since the recording also includes the information, which electrode records which kind of LFP, which can be taken into account when adjusting the stimulation, which can be provided by the same electrodes.

The system may further comprise recording means for recording electrical signals via at least one electrode, wherein the recording means are adapted to record the Local Field Potential of surrounding brain tissue to receive at least one recording of the Local Field Potential. Such a recording may be used as a reference, also called baseline recording, and may form the basis for the comparison with further recordings, e.g. in order to identify pathological abnormities in the Local Field Potential.

The baseline recording may be used to identify a target region, for example the subthalamic nucleus (STN). For example, the baseline recording can be analyzed regarding characteristics of the target region. Based on such an analysis, the baseline recording can be used for the selection of the stimulation electrodes being within the target region. It is especially possible to identify electrodes being inside of the target region on the basis of the characteristics of tissue outside of the target region. For example, as characteristic the LFP power spectral density may be used, for example there is a difference between the power spectral density of the LFP of electrodes inside the STN and outside the STN which thus forms a relatively sharp borderline in the LFP power spectral analysis. Based on this analysis, only electrodes inside the STN may be chosen for stimulation, while the other electrodes outside of the STN may remain switched off.

Moreover, the system may further comprise stimulation means for providing electrical stimulation via at least one electrode out of the plurality of electrodes, wherein the stimulation means are adapted to provide stimulation via the plurality of electrodes in at a first setup. Such a first setup may be for example a selection of a number of the electrodes that are set active, whereas the unselected electrodes are set inactive. Also, such a setup can be provided by just varying the stimulation parameters for one, some or all electrodes. By providing such a first setup, a change in the Local Field Potential may be caused and may be used as a further reference for adjusting the stimulation field.

The recording means may be further adapted to record the Local Field Potential of the surrounding brain tissue before a stimulation in at least a first setup and after the stimulation in the first setup to receive at least a first and at least a second recording of the Local Field Potential and wherein the analysis means are adapted to analyze, especially compare, the first recording and the second recording and to determine the effect of the provided stimulation of the first setup, and wherein the adjustment means are adapted to adjust the stimulation based on the comparison of the first recording and the second recording. This kind of function is based on the finding that providing stimulation to surrounding tissue will have an influence on the Local Field Potential and that a comparison of the Local Field Potential before and after stimulation allows an uncovering of the target area that needs to be stimulated. In particular, the comparison helps to identify areas in the tissue, where the Local Field Potential significantly changes due to the stimulation. The identification of these areas can be used, to intentionally steer the field in the direction of these areas, as stimulation in these areas shows beneficial effects.

The adjustment means may be adapted to semi-automatically or automatically adjust the stimulation. Semi-automatic adjustment may be understood as automatic adjustment with the restriction that the user/clinician has to manually confirm, or modify and confirm the adjustment. Automatic adjustment may be understood as adjustment, where all steps of adjustment are done by the system itself. Both adjustment approaches are advantageous, because the time required for tuning of the stimulation field and the programming of the system is significantly reduced.

The recording means may be adapted to record the Local Field Potential of surrounding brain tissue, when there is no stimulation provided by the stimulation means. During recording, the stimulation may be switched off. By this, possible effects of stimulation artifact removal procedures on e.g. the actual Local Field Potential signals can be avoided. When the stimulation is switched off, a neurophysiological carry-over effect of stimulation is likely to persist at least in the first approx. 20-60 seconds, which is reflected by the fact that parkinsonian symptoms, including rigidity and bradykinesia have not yet returned to baseline (i.e. status without stimulation; for further reference cf. e.g. Hammond C, Bergman H, Brown P. Pathological synchronization in Parkinson’s disease: networks, models and treatments. Trends Neurosci 2007; 30: 357-364).

In particular, the recording means may be adapted to record the Local Field Potential in a time frame after stimulation has ended, wherein the time frame is approx, up to 60 seconds after the stimulation, especially approx. 20 second after the stimulation.

It is also possible that the recording is done for more than e.g. 20-60 seconds. If so, the analysis (especially the calculation of the power spectral density) of the recording is done in a short sliding window of e.g. approx. 1 second with or without overlap. This will result in a spectrogram, in which the time course of the pathophysiological activity is visualized.

The recording means may be adapted to record the Local Field Potential (LFP) at least two times or more or continuously after electrical stimulation has been provided. It is also possible to compare a first LFP after stimulation and a second LFP after stimulation where second LFP is recorded e.g. less than 20-60 secs after the first recording. In such a case, the second LFP recording can form the base recording. The recording of several LFPs after stimulations further allows providing a progress analysis of the LFP from the stimulated LFP to the unstimulated LFP, which is helpful to identify in greater detail potential target areas and their characteristics. A continuous recording may be used to gain spectrograms.

The analysis means may be adapted to analyze the Local Field Potential in a spectrum between approx 0-200 Hz.

The analysis means may be adapted to analyze the Local Field Potential in a spectrum between approx. 10-45 Hz. Interestingly, it has be found that an analysis of the Local Field Potential in the spectrum between approx. 10-45 Hz is beneficial to receive data about potential target areas for stimulation. Especially in this spectrum, changes in the Local Field Potential as response to stimulation can be seen and recorded. This can be used to identify the target area with a high accuracy. If the analysis of the spatial distribution of power spectral densities of LFPs is restricted to a frequency range from especially 10 to 45 Hz, one selectively deals with the signals that originate from the STN.

The analysis means may be further adapted to divide the spectrum into at least three frequency bands. By this the accuracy of the analysis can be advantageously increased.

The first band may be between approx. 10-18.5 Hz, the second band may be between approx. 18.5-30 Hz and the third band may be between approx. 30-45 Hz.

The restriction to 18.5-30 Hz can be used to determine how to steer the current for the generation of the electrical field for stimulation in the most effective way. Furthermore, suppression effects can be detected in the frequency band between 18.5-30 Hz.

The analysis means may be adapted to determine, where a power maximum and/or minimum and/or a significant change of the Local Field Potential of the surrounding tissue is located. Such a power maximum and/or minimum of the Local Field Potential of the surrounding tissue can be used as information, where a stimulation could be beneficial and thus can be used as guidance as to where stimulation should be directed to.

The system may be capable to analyze where a maximum and/or a minimum of the LFP and/or a significant change is located, then it is e.g. possible to find out that a set of stimulation parameters on an electrode setup (which may be located outside the region of observed minimum or maximum) provides an increase of a minimum, or a decrease in a maximum, which is a desired therapeutic outcome.

The adjustment means may be adapted to provide a steering of the electrical stimulation field in the direction where the recorded power maximum and/or minimum and/or a significant change of the Local Field Potential is located. Therapeutic efficacy can subsequently be confirmed by the measurement of a reduction in the intensity of a power maximum, or an increase in the intensity of a power minimum.

Additionally, the based on the analysis, where a maximum and/or a minimum of the LFP and/or a significant change of the LFP is located, the adjustment means may be adapted to steering of the electrical stimulation field to a target region of interest, which is determined on the basis of the information, where a power maximum and/or minimum and/or a significant change of the Local Field Potential of the surrounding tissue is located.

The reduction or increase of power in the Local Field Potential can be observed in another tissue region, or in another frequency region, as the one where stimulation has been delivered.

Moreover, as a part of the present disclosure, a method of providing a neurostimulation therapy is disclosed.

Accordingly, the method comprises at least the steps of analyzing the Local Field Potential (LFP) of surrounding tissue and adjusting the direction and/or the shape of the electrical stimulation field based on the analysis of the Local Field Potential of surrounding tissue.

The method of providing a neurostimulation therapy may e.g. comprise the following steps: - Record the Local Field Potential of surrounding tissue to receive a first recording of the Local Field Potential;

Provide an electrical stimulation via a plurality of electrodes;

Record the Local Field Potential of the surrounding brain tissue again to determine the effect of the provided stimulation of the first setup to receive a second recording of the Local Field Potential; - Analyze the Local Field Potential of surrounding tissue; - Adjust the stimulation based on the comparison of the first recording and the second recording.

There may be more stimulation setups used to enhance the accuracy of the measurement of the LFP.

For example, by analyzing the first recording, i.e. the baseline recording, electrodes outside of the target region may be excluded. To do so, for example LFP powers in the range of e.g. approx. 10-45 Flz can be used to define those electrodes.

The electrical stimulation via the plurality of electrodes is adjusted based on the LFP.

The method may be performed with the system as specified above.

The method can be performed with the above described system for neurostimulation. Each functional and structural feature, either alone or in combination with other features as disclosed above and its advantages, may be also realized in connection with the method according to the present disclosure and is herewith explicitly disclosed.

Further details and advantages of the present invention shall be described hereinafter with respect to the drawings. It is shown in:

Figure 1 a schematical drawing of a neurostimulation system for deep brain stimulation (DBS);

Figure 2 a further schematical drawing of a probe of a neurostimulation system for deep brain stimulation (DBS) and its components;

Figure 3 a schematical drawing of a probe system according to the present invention;

Figure 4 a schematical drawing of the distal end of the stimulation in section A and in section B for each electrode the recorded power spectral density of the LFPs;

Figure 5 the average logarithmic LFP power spectral density across the 3 -40 Flz frequency band of all contact points at each depth (eight rows) for two patients with Parkinson’s disease (PD);

Figure 6 the relative power spectral densities between 10 - 50 Flz averaged across all contact points located inside the subthalamic nucleus (STN) for eight patients with Parkinson’s disease at baseline;

Figure 7 for each electrode the power spectral density of the LFPs at baseline;

Figure 8 the absolute power distribution into each direction for eight PD patients at baseline;

Figure 9 a variation of power spectral density in the different frequency ranges following different patterns of stimulation in a patient with Parkinson’s disease;

Figure 10 an overview of the amount of suppression and/or enhancement; and

Figure 11 spectrograms at two contact points for three different modes of current steering. A possible embodiment of a neurostimulation system 100 for deep brain stimulation (DBS) is shown in Figure 1. However, also other applications of a neurostimulation system are possible in general.

The neurostimulation system 100 comprises at least a controller 110 that may be surgically implanted in the chest region of a patient 1, typically below the clavicle or in the abdominal region of a patient 1. The controller 110 can be adapted to supply the necessary voltage pulses. The typical DBS system 100 may further include an extension wire 120 connected to the controller 110 and running subcutaneously to the skull, preferably along the neck, where it terminates in a connector. A DBS lead arrangement 130 may be implanted in the brain tissue, e.g. through a burr-hole in the skull.

Figure 2 further illustrates a typical architecture for a Deep Brain Stimulation probe 130 that comprises a DBS lead 300 and an active lead can 111 comprising electronic means to address electrodes 132 on the distal end 304 of the thin film 301, which is arranged at the distal end 313 and next to the distal tip 315 of the DBS lead 300. The lead 300 comprises a carrier 302 for a thin film 301, said carrier 302 providing the mechanical configuration of the DBS lead 300 and the thin film 301. The thin film 301 may include at least one electrically conductive layer, preferably made of a biocompatible material. The thin film 301 is assembled to the carrier 302 and further processed to constitute the lead 300. The thin film 301 for a lead is preferably formed by a thin film product having a distal end 304, a cable 303 with metal tracks and a proximal end 310. The proximal end 310 of the thin film 301 arranged at the proximal end 311 of the lead 300 is electrically connected to the active lead can 111. The active lead can 111 comprises the switch matrix of the DBS steering electronics. The distal end 304 comprises the electrodes 132 for the brain stimulation. The proximal end 310 comprises the interconnect contacts 305 for each metal line in the cable 303. The cable 303 comprises metal lines (not shown) to connect each distal electrodes 132 to a designated proximal contact 305.

Figure 3 shows schematically and in greater detail an embodiment of a system 100 for brain applications, here for neurostimulation and/or neurorecording as a deep brain stimulation system 100 as shown in Figures 1 and 2. The probe system 100 comprises at least one probe 130 for brain applications with stimulation and/or recording electrodes 132, wherein e.g. 40 electrodes 132 can be provided on outer body surface at the distal end of the probe 130. By means of the extension wire 120 pulses P supplied by controller 110 can be transmitted to the active lead can 111. The controller 110 can be an IPG 110.

The electrodes 132 are adapted for both stimulation and recording.

Furthermore, the electrodes 132 form an array of electrodes positioned at different axial positions along the length of the lead 300, as well as at different angular positions about the circumference of e.g. lead 300 of the neurostimulation system 100.

The system for neurostimulation 100 comprises analysis means 320, adjustment means 322, recording means 324 and stimulation means 326.

Also, the system 100 comprises electronics E, i.e. at least one controller to control the analysis means 320, adjustment means 322, recording means 324 and stimulation means 326.

The electronics E can be arranged in active lead can 111, but it is also possible, that the electronics are at least partially arranged in the IPG 110.

The analysis means 320, adjustment means 322, recording means 324 and stimulation means 326 may be arranged in the active lead can 111, but it is also possible, that they are at least partially arranged in the IPG 110.

The analysis means 320 are to analyze a Local Field Potential LFP of surrounding tissue, here brain tissue.

The adjustment means 322 are adapted to adjust the direction and/or the shape of the electrical stimulation field based on the analysis of the Local Field Potential of surrounding tissue.

The recording means 324 are adapted for recording electrical signals via at least one of the electrodes 132, wherein the recording means 324 are adapted to record the Local Field Potential LFP of surrounding tissue to receive at least one recording of the Local Field Potential LFP.

The stimulation means 326 are adapted for providing electrical stimulation via at least one electrode out of the plurality of electrodes 132, wherein the stimulation means 326 are adapted to provide stimulation via the plurality of electrodes 132 in at a first setup, second setup, etc..

As already mentioned above, Local Field Potentials (LFPs) are the low frequency (< 500 Hz) fluctuations in extracellular electrical activity on top of which the neuronal spikes are superimposed, which may give rise either to depolarization or hyperpolarization of ensembles of neurons. The synchronous firing of ensembles of neurons is reflected in the frequency components of the LFPs, particularly in the higher frequency ranges.

As such, it has been demonstrated that, inside the subthalamic nucleus (STN), LFPs show a relationship with the envelope of the neural spiking pattern. Also, the LFP signals recorded inside the parkinsonian STN show changes in spectral density that are related to the on or off state of the patient or that are related to certain motor tasks. Most studies about LFPs in the STN make distinction between low-beta (13-20 Hz), high beta (20-30 Hz) or gamma rhythms (30 - 80 Hz) and have demonstrated interactions between these different frequency bands.

Therefore, instead of using the spiking pattern of several neurons from the micro electrode recording (MER) during DBS surgery, the LFPs could be used to localize the STN. This should give the advantage that prior to placement of the DBS lead, for refinement of the STN localization, no MER would be required, but localization of the STN could be directly derived from the LFPs recorded from the same contacts that are used for chronic DBS.

Moreover, when more knowledge would be available about the relationship between the frequency characteristics of LFPs and clinical symptomatology and level of medication, this could also be used to optimally adapt neurostimulation, here deep brain stimulation based on LFP feedback.

The STN is nowadays a commonly used target of DBS for PD. There is growing evidence that abnormal oscillatory electrical activity of ensembles of neurons in the STN is related to the severity of the parkinsonian state of the patient. Since the power of the Local Field Potential (LFP) recordings is correlated to clinical outcome and electrical activity of ensembles of neurons in the STN, the fingerprint of a stimulation-pattern on LFP spectra can be used to automatically identify optimal mode of stimulation. However, the use of certain characteristic of the LFP signal for both intra-operative functional localization and post-operative feedback for stimulation configuration have not been accomplished yet in standard procedures of DBS surgery. An important reason for this is that current DBS leads do have a rather coarse spatial resolution with a relative large contact (e.g. length of 1.5 mm; surface of 6.0 mm2) and with a rather large inter-contact distance (e.g. 2 mm) compared to the size of the STN (mean diameter of 4-6 mm). Moreover, the relevant oscillatory activity which should be used for localization and stimulation feedback is probably confined to the even smaller sensorimotor part of the STN. Finally, due to volume conduction properties of the brain tissue, these rather large contacts may pick up also electrical activity of areas more remotely located from the surface of the contact, which may introduce an extra inaccuracy in localization of pathological motor related activity.

In particular, the system 100 for neurostimulation according to the present disclosure, here a deep brain stimulation system 100 (as e.g. shown in Figure 3), comprises a plurality of electrodes 132 being adapted for generating an electrical stimulation field, analysis means 320 being adapted to analyze the Local Field Potential LFP of surrounding tissue and adjustment means 322 being adapted to adjust the direction and/or the shape of the electrical stimulation field based on the analysis of the Local Field Potential of surrounding tissue.

The recording means 324 are further adapted to record the Local Field Potential (LFP) of the surrounding tissue before a stimulation in at least a first setup and after the stimulation in the first setup to receive at least first and at least a second recording of the Local Field Potential (LFP) and wherein the analysis means (320) are adapted to analyze, especially compare, the first recording and the second recording and to determine the effect of the provided stimulation of the first setup, and wherein the adjustment means 322 are adapted to adjust the stimulation based on the comparison of the first recording and the second recording. Especially, the recording means 324 are adapted to record the Local Field Potential (LFP) of surrounding tissue, when there is no stimulation provided by the stimulation means 326.

The recording means are also adapted to record the Local Field Potential (LFP) at least two times or more or continuously after electrical stimulation has been provided.

The analysis means 320 are adapted to analyze the Local Field Potential in a spectrum between approx. 10-45 Hz.

The adjustment means 322 are adapted to semi-automatically or automatically adjust the stimulation.

The analysis means 320 are further adapted to divide the spectrum into three frequency bands B1, B2, B3.

The first band B1 is between approx. 10-18.5 Hz, the second band B2 is between approx. 18.5-30 Hz and the third band B3 is between approx. 30-45 Hz.

The analysis means 320 are adapted to determine, where a power maximum of the Local Field Potential LFP of the surrounding tissue is located.

The adjustment means 322 are adapted to provide a steering of the electrical stimulation field in the direction where the recorded power maximum of the Local Field Potential (LFP) is located.

The system in general is capable to analyze where a maximum and/or a minimum of the LFP and/or a significant change is located, then it is e.g. possible to find out that a set of stimulation parameters on an electrode setup (which may be located outside the region of observed minimum or maximum) provides an increase of a minimum, or a decrease in a maximum, which is a desired therapeutic outcome.

The adjustment means in general are adapted to provide a steering of the electrical stimulation field in the direction where the recorded power maximum and/or minimum and/or a significant change of the Local Field Potential is located. Therapeutic efficacy can subsequently be confirmed by the measurement of a reduction in the intensity of a power maximum, or an increase in the intensity of a power minimum.

Additionally, the based on the analysis, where a maximum and/or a minimum of the LFP and/or a significant change of the LFP is located, the adjustment means are adapted to steering of the electrical stimulation field to a target region of interest, which is determined on the basis of the information, where a power maximum and/or minimum and/or a significant change of the Local Field Potential of the surrounding tissue is located.

The lead design of a system for neurostimulation 100 according to the present disclosure makes it possible to perform simultaneous LFP recordings in the STN at different depths and in different directions with a much higher resolution without moving the electrode, providing multidirectional spatial and temporal information about disease-related electrical activity and the effect of stimulation, see Figure 4. Across the contacts that were localized inside the STN, a rather large variability of the LFP power spectral density (PSD) in direction, depth and distribution has been observed, see Figure 4.

Figure 4 shows in section A a schematic via of the stimulation lead 300 with the complex array of electrodes 132. The depicted lead carries in this embodiment 32 oval disc-shaped electrode contacts (approx. 0.66 x 0.80 mm) arranged on 8 rows of 4 contacts, covering a total length of 6.0 mm. Section B of Figure 4 shows for each electrode 132 the power spectral density of the LFPs between 0 and 40 Hz prior any stimulation in the unfolded 2D array display in a patient with Parkinson’s disease. Based on the MER recordings in this case all 32 contacts were completely inside the STN. On top of the array, the direction towards which each contact is heading is indicated. (For instance, contact 1,9,17 and 25 are heading into the anterior direction). The contact points 24 and 28 boxes are filled with a red cross because here LFP recordings were not possible.

Power spectral densities prior any stimulation show a multimodal distribution with peaks in the 3-10 Hz, 10-18 Hz and 18.5-30 Hz frequency bands. However, LFP recordings from the multi contact DBS lead show enhanced power spectral densities in the 10-45 Hz frequency band inside the STN compared to outside the STN, see Figure 5. Thus, the border of the STN can be detected with the SSM lead using LFP power with a frequency between 10 and 45 Hz.

Figure 5 shows the average logarithmic LFP power spectral density across the 3 - 40 Hz frequency band of all contact points at each depth (eight rows) for two PD patients. For clarity the distal end of the new 32-contact DBS lead is shown at the right. The white dotted line B (i.e. borderline B) indicates the start of the STN as extrapolated by MER.

The baseline recording may be used to identify a target region, for example the subthalamic nucleus (STN). For example, the baseline recording can be analyzed regarding characteristics of the target region. Based on such an analysis, the baseline recording can be used for the selection of the stimulation electrodes being within the target region. It is especially possible to identify electrodes being inside of the target region on the basis of the characteristics of tissue outside of the target region. For example, as characteristic the LFP power spectral density may be used, for example there is a difference between the power spectral density of the LFP of electrodes inside the STN and outside the STN which thus forms a relatively sharp borderline B (see Figure 5) in the LFP power spectral analysis. Based on this analysis, only electrodes inside the STN may be chosen for stimulation, while the other electrodes outside of the STN may remain switched off.

Figure 6 shows the relative power spectral densities (PSD) between 10 - 50 Hz averaged across all contact points located inside the STN for eight PD patients at baseline.

The average LFP PSD of all contacts inside the STN suggests a subdivision into two different frequency bands between 10-30 Hz with a bimodal spectral distribution, see Figure 6. Therefore, analysis of the LFP spectrum between 10-45 Flz should be performed on three separate frequency bands 1) from 10-18 Flz 2) from 18.5-30 Flz 3) from 30-45 Flz. Contact points that are located inside the STN show that the LFP power in the 10-45 Flz frequency range depends on the recording direction and the depth, which points to the presence of small cell clusters within the STN that have specific pathophysiological activity (Figure 7 and 8). Such a precise localization of small cell clusters is not possible with the currently available electrodes, which can only record LFPs from a relatively large spherical area.

Figure 7 shows the power spectral density of the LFPs at baseline of a PD patient in the unfolded two dimensional array for each electrode 132 of the lead 300 (above each diagram the number of the electrode is mentioned). On top of the array, the direction towards which each contact is heading is indicated.

Figure 8 shows the absolute power distribution into each direction for eight PD patients at baseline. Power has been averaged along the contact points lying inside the STN for eight columns. Next to these ‘spiderplots’ the final DBS electrode position is shown in an axial display on the early postoperative CT fused to the preoperative MRI at the level of the STN.

Depending on stimulation field shape/direction, different effects on LFP spectra are obtained; e.g. enhancement or reduction of power in the three frequency bands could be achieved. In general, suppression always is observed in the frequency band from 18.5-30 Flz, irrespective of stimulation pattern, whereas also enhancement of LFP power during anterior, posterior, lateral or medial steering has been observed in the 10-18 Flz and the 30.5-45 Flz frequency bands. Enhancement in spherical mode never has been observed (Figure 9, 10 and 11). Moreover, comparing the spatial distribution of the power spectral density in the 18.5-30 Flz range (figure 8) with the amount of suppression for different steering modes (Figure 10), several patients show highest suppression with a steering mode in the direction where the power is highest. Thus, if analysis of the LFP spectrum is restricted to the 18.5-30 Flz, it could be used to determine how to steer the current in the most effective way through a selection of the contact points.

Figure 9 shows a variation of power spectral density in the different frequency ranges following different patterns of stimulation in a PD patient. In the left column for contact 8 and in the right column for contact 26, power spectral densities are shown at baseline (green) and at a 15 second period just prior to anterior, posterior and ring stimulation and 15 seconds immediately after anterior, posterior and ring stimulation.

Figure 10 shows for six patients at each of the three frequency bands between 10-45 Hz the amount of suppression and/or enhancement, averaged across all electrodes inside the STN, after spherical stimulation and anterior, lateral, posterior and medial steering. The images on top indicate the spatial distribution of the electrical field in the different steering modes.

Figure 11 shows spectrograms at two contact points for three different modes of current steering, i.e. anterior, posterior and spherical mode in a PD patient. A spectrogram is a continuous, color-coded representation of the time evolution of the spectral power density of the LFP. A horizontal line through a spectrogram provides the time-evolution for a single frequency band. A vertical line provides an instantaneous power density spectrum at that given time.

The dark vertical bar indicates the division between pre and post stimulation period. Light grey bars indicate periods with artefacts. Dark sections indicate high power, medium grey sections indicate intermediate power and light grey sections indicate low power. Anterior steering does not lead to so much suppression of power, than posterior and spherical mode steering.

After stimulation with posterior steering there is an enhancement in the 30-45 Hz frequency band, whereas in the other parts of the spectrum there is suppression. Also, it can be seen that 10-20 seconds after stimulation has been stopped, suppression of power in the 10-18 Hz band as well as the 18.5-30 Hz band diminishes.

Here follows the translation of the Dutch text on the next pages: 1. A system (100) for neurostimulation at least comprising a plurality of electrodes (132) being adapted for generating an electrical stimulation field, analysis means (320) being adapted to analyze the Local Field Potential (LFP) of surrounding tissue and adjustment means (322) being adapted to adjust the direction and/or the shape of the electrical stimulation field based on the analysis of the Local Field Potential of surrounding tissue. 2. The system (100) of claim 1, wherein the system (100) comprises recording electrodes (132). 3. The system (100) of claim 2, wherein the recording electrodes are at least partially a part of the plurality of electrodes (132), especially wherein the plurality of electrodes (132) is adapted for both stimulation and recording. 4. The system (100) according to one of the preceding claims, wherein the system (100) further comprises recording means (324) being adapted for recording electrical signals via at least one electrode (132), wherein the recording means (324) are adapted to record the Local Field Potential (LFP) of surrounding tissue to receive at least one recording of the Local Field Potential (LFP). 5. The system (100) according to claim 4, wherein the at least one recording is a baseline recording and wherein the analysis means are further adapted to use the baseline recording for identifying the location of the electrodes. 6. The system (100) according to one of the preceding claims, wherein the system (100) further comprises stimulation means (326) being adapted for providing electrical stimulation via at least one electrode out of the plurality of electrodes (132), wherein the stimulation means (326) are adapted to provide stimulation via the plurality of electrodes (132) in at least a first setup. 7. The system (100) according claim 5 and 6, wherein the recording means are further adapted to record the Local Field Potential (LFP) of the surrounding tissue before a stimulation in at least a first setup and after the stimulation in the first setup to receive at least first and at least a second recording of the Local Field Potential (LFP) and wherein the analysis means (320) are adapted to analyze, especially compare, the first recording and the second recording and to determine the effect of the provided stimulation of the first setup, and wherein the adjustment means (322) are adapted to adjust the stimulation based on the comparison of the first recording and the second recording. 8. The system (100) according to claims 5 and 6 or 7, wherein the recording means (324) are adapted to record the Local Field Potential (LFP) of surrounding tissue, when there is no stimulation provided by the stimulation means (326). 9. The system (100) according to one of claims 6 to 8, wherein the recording means are adapted to record the Local Field Potential (LFP) at least two times or more or continuously after electrical stimulation has been provided. 10. The system (100) according to one of the preceding claims, wherein the adjustment means (322) are adapted to semi-automatically or automatically adjust the stimulation. 11. The system (100) according to one of the preceding claims, wherein the analysis means (320) are adapted to analyze the Local Field Potential in a spectrum between approx. 10-45 Flz. 12. The system (100) according to claim 11, wherein the analysis means (320) are further adapted to divide the spectrum into three frequency bands (B1, B2, B3). 13. The system (100) according to claim 12, wherein the first band (B1) is between approx. 10-18.5 Hz, the second band (B2) is between approx. 18.5-30 Hz and the third band (B3) is between approx. 30-45 Hz. 14. The system (100) according to one of the preceding claims, wherein the analysis means (320) are adapted to determine, where a power maximum and/or power minimum and/or a significant change of the Local Field Potential (LFP) of the surrounding tissue is located. 15. The system (100) of claim 14, wherein the adjustment means (322) are adapted to provide a steering of the electrical stimulation field in the direction where the recorded power maximum and/or power minimum and/or significant change of the Local Field Potential (LFP) is located and/or to provide steering of the electrical stimulation field to a target region of interest, which is determined on the basis of the information, where a power maximum and/or minimum and/or a significant change of the Local Field Potential of the surrounding tissue is located.

Claims (15)

A neurostimulation system (100) comprising at least a plurality of electrodes (132) adapted to generate an electrical stimulation field, analyzing means (320) adapted to analyze the local field potential (Local Field Potential LFP) of surrounding tissues and adjustment means (322) adapted to adjust the direction and / or shape of the electrical stimulation field based on the analysis of the local field potential of surrounding tissues. The system (100) of claim 1, wherein the system (100) comprises recording electrodes (132). The system (100) of claim 2, wherein the recording electrodes are at least in part a portion of the plurality of electrodes (132), in particular the plurality of electrodes (132) being arranged for both stimulation and recording. The system (100) according to any one of the preceding claims, wherein the system (100) further comprises recording means (324) adapted to record electrical signals via at least one electrode (132), the recording means (324) being adapted to register the local field potential (LFP) of surrounding tissues to receive at least one local field potential (LFP) registration. The system (100) of claim 4, wherein the at least one record is a baseline record and wherein the analysis means is further adapted to use the baseline record to identify the location of the electrodes. The system (100) of any preceding claim, wherein the system (100) further comprises stimulation means (326) adapted to provide electrical stimulation through at least one electrode of the plurality of electrodes (132), the stimulation means (326) ) are arranged for stimulation via the plurality of electrodes (132) in at least a first start-up. The system (100) according to claims 5 and 6, wherein the recording means is further adapted to record the local field potential (LFP) of the surrounding tissue prior to stimulation in at least a first start-up and after stimulation in the first start-up before registering at least a first and at least a second registration of the local field potential (LFP) and wherein the analysis means (320) are arranged for analyzing, in particular comparing, the first registration and the second registration and determining the effect of the received stimulation of the first start-up, and wherein the setting means (322) are adapted to adjust the stimulation based on the comparison of the first registration and the second registration. The system (100) according to claims 5 and 6 or 7, wherein the recording means (324) is adapted to record the local field potential (LFP) of surrounding tissues if there is no stimulation by the stimulation means (326) The system (100) according to any of claims 6 to 8, wherein the recording means are arranged to record the local field potential (LFP) at least twice or more or continuously after electrical stimulation has been delivered. The system (100) according to any one of the preceding claims, wherein the adjustment means (322) are arranged for semi-automatic or automatic adjustment of the stimulation. The system (100) of any one of the preceding claims, wherein the analyzing means (320) is adapted to analyzing the local field potential (LFP) in a spectrum between about 10-45 Hz. The system (100) of claim 11, wherein the analyzing means (320) is further adapted to divide the spectrum into three frequency bands (B1, B2, B3). The system (100) of claim 12, wherein the first band (B1) between approximately 10-18.5 Hz, the second band (B2) between approximately 18.5-30 Hz and the third band (B3) between approximately 30-45 Hz. The system (100) of any one of the preceding claims, wherein the analyzing means (320) is arranged to determine where a maximum power and / or minimum power and / or a significant change in the local field potential (LFP) of the surrounding tissue is located. The system (100) of claim 14, wherein the adjusting means (322) are adapted to control the electrical stimulation field in the direction in which the recorded current is maximum and / or minimum power and / or the significant change of the local field potential (LFP) is located and / or provides direction of the electrical stimulation field to a target area of interest, which is determined based on the data, where a power maximum and / or minimum and / or a significant change of the local field potential (LPF) of the surrounding tissue.